The protein kinases are a large family of proteins which play a central role in the regulation of key cellular processes. Disregulation of protein kinases activity can lead to oncologic, chronic inflammatory diseases, CNS diseases etc. A list of kinases with validated preclinical or clinical therapeutic impact includes: ABL1, AKT, AKT2, AURKA, BRAF, BCR-ABL, BLK, BRK, C-KIT, C-MET, C-SRC, CAMK2B, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CRAF1, CHEK1, CHEK2, CLK1, CLK3, CSF1R, CSK, CSNK1G2, CSNK1G3, CSNK2A1, DAPK1, DAPK2, DAPK3, EGFR, EPHA2, EPHA3, EPHA5, ERBB2, ERBB3, ERBB4, ERK, ERK2, ERK3, FES, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, FGR, FLT-1, FYN, GSK3B, HCK, IGF1R, INSR, ITK, JAK1, JAK2, JAK3, JNK1, JNK2, JNK3, KIT, LCK, LOK, MAP3K5, MAPKAPK2, MARK1, MEK1, MEK2, MET, MKNK2, MST1, NEK2, p38-alpha, p38-delta, p38-gamma, PAK1, PAK4, PAK6, PAK7, PDPK1, PDGFR, PIK3CG, PIM1, PIM2, PKC, PLK1, PLK4, PRKCQ, PRKR, PTK2, PTK2B, RET, ROCK1, ROS, RPS6KA1, SLK, SRC, SRPK1, STK16, SYK, TAK1, TGFBR1, TIE, TIE2, TNK2, TRK, VEGFR2, WEE1, ZAP70 (Michal Vieth et al, Kinomics: characterizing thetherapeutically validated kinase space, Drug Discov Today•Volume 10, Number 12•June; Oleg Fedorov, The (un)targeted cancer kinome, nature chemical biology, 2010, 6, 166-169; 2005; Matthias Gaestel; Targeting innate immunity protein kinase signalling in inflammation, Nat REv Drug Discov, 480-499, 2009 (8); Karaman M W et al, A quantitative analysis of kinase inhibitor selectivity, Nat. Biotechnol. 2008 January; 26(1):127-132; Fabian M A, et al, A small molecule-kinase interaction map for clinical kinase inhibitors, Nat. Biotechnol. 2005 March; 23(3):329-336; Bhagwat S S, Kinase inhibitors for the treatment of inflammatory and autoimmune disorders. Purinergic Signal. 2009 March; 5(1):107-15; Friedrich Grimminger et al, Targeting non-malignant disorders with tyrosine kinase inhibitors, Nature Reviews Drug Discovery 9, 956-970). With the advent of new experimental data, this list is constantly growing.
Application of small molecule protein kinase inhibitors represents a prospective approach for the treatment of diseases associated with impaired protein kinase activity. Examples of such inhibitors approved for clinical use are: Imatinib, Nilotinib, Dasatinib, Sunitinib, Sorafenib, Lapatinib, Gefitinib, Erlotinib, Flavopiridol. A lot of clinical candidate kinase inhibitors undergoes clinical trials and preclinical development.
Widespread use of small molecule protein kinase inhibitors in clinic revealed several serious issues related to their efficacy and safety. First these problems are connected with low activity of inhibitors towards mutated protein kinase forms that may eventually occur in patients. For instance it is well known that kinase domain of gene product of BCR-ABL chronic myelogenous leukemia target is subjected to mutations that cause resistance to imatinib (mutations Y253H, E255V, T315I) (Timothy Hughes et al, Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results, BLOOD, 2006; 108:28-37 and second generation inhibitors Nilotinib and Dasatinib (mutation T315I) (Elias Jabbour, Long-term outcome of patients with chronic myelogenous leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations, Blood. 2009; 114:2037-2043). Second, kinase inhibition selectivity plays an important role. As a rule decrease in selectivity leads to decrease in inhibitor's safety as can be judged by comparison of more selective imatinib and less selective dasatinib both used for the treatment of chronic myelogenous leukemia. Third, bioavailability of kinase inhibitors has a big impact. Several inhibitors of the same Abl kinase possess low bioavailability: dasatinib (bioavailability 14-34%, Amrita V. K. et al. Cancer Chemoter Pharmacol 2008, 61, 365-376), nilotinib (bioavailability 30%, Nilotinib Prescribing Information, Novartis), ponatinib (bioavailability 20%, J. Med. Chem. 2010, 53, 4701-4719). Thus the development of kinase inhibitors with improved bioavailability is a practically important task.
There are imidazole derivatives which possess inhibiting action upon abnormal activity of kinases selected from Abl, BCR-AbI, PDGF-R, trkB, c-SRC, BMX, FGFR3, b-RAF, SGK, Tie2, Lck, JNK2a2, MKK4, c-RAF, MKK6, SAPK2a and SAPK2P and pharmaceutical composition comprising these compounds for treatment or prevention of such diseases as proliferative disorders and diseases resulting from inadequate activation of immune and nerve systems (Russian patent 2401265). This source may be referred as the nearest analogue.